AU757177B2 - New 4-substituted piperidines - Google Patents
New 4-substituted piperidines Download PDFInfo
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- AU757177B2 AU757177B2 AU59366/99A AU5936699A AU757177B2 AU 757177 B2 AU757177 B2 AU 757177B2 AU 59366/99 A AU59366/99 A AU 59366/99A AU 5936699 A AU5936699 A AU 5936699A AU 757177 B2 AU757177 B2 AU 757177B2
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
I U
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Faes. Fabrica Espanola de Productog Quimicas Y Farmaceuticos S.A.
ADDRESS FOR SERVICE: DAVIES COLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.
INVENTION TITLE: New 4-substituted piperidines The following statement is a full description of this invention, including the best method of performing it known to me/us:- IP Australia Documents received on: 0 I1 NOV 1S99
CD
Batch No: la Introduction In recent years, selective serotonin reuptake inhibitors (SSRIs) have started to be used for treating depression and other central nervous system disorders, noteworthy among which are fluoxetine, citalopram, sertraline and paroxetine. They all have different chemical structures, which helps to explain their different metabolic and pharmacokinetic profiles. Their performance as antidepressants compares with that of classic tricyclic compounds, but their advantage is that they are safer and better tolerated.
The present invention relates to a number of new 4-substituted piperidines having an aryloxy functionality and potently inhibiting serotonin and/or noradrenaline reuptake, as a result of their high affinity for their neuronal transporters. This characteristic provides them with an enhanced antidepressant potential in human therapy. Other potential therapeutic applications of these compounds are treatment of nervous bulimia, alcohol addiction, anxiety, obsessive-compulsive disorders, panic, pain, pre-menstrual syndrome and social phobia, as well as migraine prophylaxis.
Bibliography also describes other piperidine derivatives with aryloxy functionality as potential antidepressants, albeit with a chemical nature differing essentially from those claimed herein, since the piperidine is substituted at the 3-position. That is for instance the case of such compounds as 3-[(2-methoxyphenoxy)phenyl]methyl-piperidine 1 (Melloni, Carniel, Della 20 Torre, Bonsignalari, Buonamici, Pozzi, Ricciardi, Rossi, A.C. Eur. J Med.
Chem. Chim. Ther. 1984, 3, 235-242; Melloni, Della Torre, De Munari, Meroni, M., STonani, R. Gazetta Chimica Italiana 1985, 115, 159-163) and 3-[(phenoxy)phenyl]methylpiperidine 2 (FR 2,010,615 CA73; 66442j; GB 1,203,149 CA73: 120509b). In these compounds, the substitution of the piperidine ring at the 3-position results in an additional chiral centre. The 25 presence of the two chiral centres results in diastereomeric mixtures, which is the form in which the preparation of these compounds I N H
H
2 has been described. The preparation and/or isolation of pure enantiomers is not described in any case. However, the compounds claimed in the present specification possess a single chiral centre, I -2since they have the piperidine ring substituted at the 4-position. They have been prepared as racemic mixtures and as pure enantiomers, using synthetic methods differing from those used in preparing I and 2.
Moreover, other piperidine derivatives having aryloxy functionality and the piperidine ring substituted at the 4-position have been described as potential antidepressants (formulae 3 and 4).
Thus, in the case of 3 type compounds (JP 96 40,999 CA124: 343333n),
H-N
a
O
Q R H-N H-O 3 4 the aryloxy group is directly joined to the piperidine ring, whereas in the 4 type compounds (JP 96 40,999 CA124: 343333n) said group is joined to the piperidine ring through a methylene group which has no further substitutions. The compounds described herein differ largely from those, since they have the aryloxy group joined to the piperidine ring through a methylene group wherein, in all cases, one of the methylene group hydrogens is substituted by an aryl group, substituted or not, as defined hereinafter. These compounds are therefore structurally different from the 3 and 4 types and the synthetic methodology used in preparing the same is also absolutely different.
20 Description The new 4-substitude piperidines described in the present invention are represented by general formula in which groups R 1 and R 2 are non-substituted aryl radicals or aryl radicals mono- or poly-substituted with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, trifluoromethoxy, trifluoromethyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaryl and 25 carbonylamino.
H-N Ri
(I)
i The compounds of general formula have an asymmetric centre and have been prepared as racemic mixtures and as pure enantiomers. The present invention includes all optical isomers of the compounds of general formula and racemic mixtures thereof. The present invention also comprises the pharmaceutically acceptable salts of these compounds with inorganic acids (such as: hydrochloric, hydrobromic, nitric, sulphuric and phosphoric) and with organic acids (such as: acetic, fumaric, tartaric, oxalic, citric, p-toluenesulphonic and methanosulphonic).
The racemic compounds of general formula were prepared using well-known synthetic methods starting with the compounds of general formula (II).
Formation of the alkylarylether group was carried out using the Mitsunobu reaction (Mitsunobu, 0. Synthesis 1981, 1; Hughes, D.L. Organic Reactions 42, 335) with phenols R 2 -OH, in which R 2 is an aryl radical, substituted or not, as described for general formula and the compounds of general formula in which R 1 is an aryl radical, substituted or not, as described for general formula and R 3 is hydrogen or R 4 which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl.
OH
R
3 -N o -R
(II)
The alkylarylether group was also prepared using an aromatic nucleophilic substitution reaction (Berglund, R.A. Org. Proc. Res. Dev. 1997 1, 328-330) with the compounds of general formula (II) defined above, and the fluorinated derivatives R 2 in which R2 is an aryl radical mono- or 2 poly-substituted with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, 20 trifluoromethoxy, trifluoromethyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaryl and carbonylamino. The compounds of general formula (II) were prepared using conventional synthetic methods, starting with the compounds of general formula (III) (Duncan, Helsley, Welstead, DaVanzo, Funderburk, Lunsford, C.D. J. Med. Chem. 1970, 13 in which R5 is an acetyl radical, ethoxycarbonyl and R 6 is cyano or carboxy.
IRs-NI-R6
(II)
The compounds of general formula (III) defined above were transformed into the compounds of 30 general formula in which RI is an aryl radical, substituted or not, RT-N R1
(IV)
as described for the compounds of general formula and R7 is hydrogen, acetyl or R 4 which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. Such transformation was made using two reaction types: a) a Friedel-Crafts reaction of the acid chlorides derived from the compounds of general formula (111), in which Rs is an acetyl or ethoxycarbonyl and R6 is carboxy (Duncan, Helsley, Welstead, DaVanzo, Funderburk, W.H., Lunsford, C.D. J. Med Chem. 1970, 13 1) with benzene or conveniently functionalised derivatives thereof; or b) a Grignard reactive addition reaction, prepared from conveniently functionalised aryl halides, to compounds of general formula (III) in which Rs is acetyl, ethoxycarbonyl or t-butoxycarbonyl and R6 is cyano (Duncan, Helsley, Welstead, DaVanzo, Funderburk, Lunsford, C.D. J. Med. Chem. 1970, 13 1).
Reduction of the compounds of general formula (IV) described provides the general formula (II) alcohols defined above.
The enantiomers composing the racemic mixtures of general formula were obtained using two different pathways: a) resolution of the corresponding racemic mixture by split crystallisation of the diastereomeric salts prepared with chiral acids (D or L-dibenzoyltartaric, D or L-tartaric, D or Ldi-p-toluyltartaric and D or L-mandelic) and b) enantioselective synthesis. In the latter case, the enantiomers of general formula were obtained by reacting phenols R 2 -OH or the fluorinated aromatic derivatives R 2 -F defined above, with the enantiomers of the general formula (II) alcohols, as described for the racemic mixtures of general formula In the enantiomers of the 20 general formula (II) alcohols, RI is an aryl radical, substituted or not, as defined for the •compounds of general formula and R 3 is hydrogen or R 4 which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. The enantiomers of the general formula (II) alcohols defined above were obtained by enantioselective reduction (Ramachandran, P.V., Teodorovic, Rangaishenvi, Brown, H.C. J. Org. Chem. 1992, 57, 2379-2386) of the 25 compounds of general formula (IV) (Duncan, Helsley, Welstead, DaVanzo, J.P., Funderburk, Lunsford, C.D. J. Med Chem. 1970, 13 in which RI is an aryl radical, substituted or not, as defined for the compounds of general formula and R 7 is hydrogen or R4, "defined above.
The pharmacological activity of the compounds of general formula was determined using well- 30 established in vitro and in vivo pharmacological processes. The affinity of the compounds for the serotonin reuptake receptors (5HT) was evaluated in full rat cerebral cortex, using ['H]-paroxetine as radioligand (Habert, Graham, Tahraoui, Claustre, Langer, S.Z. Eur J Pharmacol.
1985, 118, 107-114) yielding Ki values ranging between 0.5 and 500 nmol/1. The affinity of the compounds for noradrenaline (NA) reuptake receptors was evaluated in full rat cerebral cortex, using ['H]-nisoxetine as radioligand (Tejani-Butt, J. Pharmacol. Exp. Ther. 1992, 260, 1, 427-436), yielding Ki values ranging between I and 500 nmol/I. The following were used as assays predicting antidepressant activity: mouse tail suspension (Steru, Chermat, Thierry, Mico, Lenegre, St6ru, Simon, Porsolt, R.D. Prog. Neurophsychopharmacol.
Biol. Psychiat. 1987, 11, 659-671), rat or mouse desperate behaviour (Porsolt, Anton, G., Blavet, Jalfre, M. Eur. J. Pharmacol. 1978, 48, 379-394) and enhancing rat yohimbine induced lethality (Quinton, Brit. J. Pharmacol. 1963, 21, 51-66). The compounds with Ki ranging between 0.5 and 40 nmol/l, for one of the transporters or for both, displayed an excellent antidepressant activity in the three models when administered within the 1 to 30 mg/Kg range orally, intraperitoneally or subcutaneously.
The following examples illustrate the scope of the present invention, which is not howsoever limited to such examples.
Example 1 (+/-)-4-[(4-trifluoromethoxyphenoxy)-2-(4-fluorophenyl)]methyl-piperidine, fumarate A mixture of (+/-)-4-[(4-trifluoromethoxyphenyl)hydroxy]methyl- -piperidinecarboxylic acid, 1,1-dimethyl-ethylester (2.25 g, 7.27 mmol), 2-pyridyl-diphenylphosphine (1.90 g, 7.27 mmol) and 1.3 g (7.4 mmol) of 4-trifluoromethoxyphenol in 40 mL of tetrahydrofurane (THF) was treated with a solution of diethyl-aza-dicarboxylate (DEAD) (1.15 mL) in 10 mL of THF. The reaction mixture was stirred at 20 0 C for 4-6 h and concentrated. The residue was dissolved in ethyl ether, washed with an aqueous HCI solution and an aqueous NaOH solution, dried 20 (anh. Na 2
SO
4 filtered and concentrated. 2.4 g were obtained of an oil which was dissolved Sin dichloromethane (50 mL) and treated with a solution of trifluoroacetic acid (2.1 mL) in 10 mL of dichloromethane. After 20 h at 20 0 C, this was washed with an aqueous NaOH solution and saturated aqueous NaCI solution. Drying (anh. Na 2
SO
4 filtering and concentration provided 1.3 g of the product, which was suspended in anhydrous ether (60 mL) and treated with 25 fumaric acid (0.42 yielding 1.0 g of the fumarate (60% yield) with a m.p. 130-134 0 C. The RMN-'H (DMSO-d 6 displayed a characteristic signal at 4.31 ppm J= 5.9 Hz, 1H, CHOAr) and RMN-"C (DMSO-d 6 displayed at 74.9 ppm a signal corresponding to CHOAr carbon.
Example 2 (+/-)-4-[(4-fluorophenoxy)(4-fluorophenyl)]methyl-piperidine, hydrochloride i: 30 A mixture of (+/-)-4-[(4-fluorophenyl)hydroxy]methyl-l-piperidinecarboxylic acid, 1,1-dimethylethylester (16.33 mmol) and 1.9 g of 4-fluorophenol in 50 mL of THF was treated with 5.0 g of triphenylphosphine and a DEAD solution (3.45 mL) in 10 mL of THF was then added. After 3 h, the solvent was distilled and the resultant oil was treated with hexane, yielding a precipitate which was filtered. The filtrate was concentrated and the residue dissolved in dichloromethane (100 mL) and treated with a trifluoroacetic acid solution (8 mL) in 30 mL of dichloromethane. After 15 h, -6the reaction was worked as usual and the hydrochloride was prepared in THF, yielding 3.6 g thereof as an amorphous and slightly hygroscopic rose-coloured solid (Yield: 70%) with a m.p. 0 C RMN-'H (CDCI 3 of the hydrochloride displayed a characteristic signal at 4.72 ppm (d, J 5.8 Hz, CHOAr) and RMN-" C (CDCI 3 a signal at 83.1 ppm corresponding to CHOAr carbon.
The following compounds were analogously prepared: (+/-)-4-[(4-fluorophenoxy)(4-chlorophenyl)]methyl-piperidine, hydrochloride (54% yield, hygroscopic), (+/-)-4-[(4-methoxyphenoxy)(4-fluorophenyl)]methyl-piperidine, fumarate (60% yield, m.p. 139-142oC), (+/-)-4-[(4-trifluoromethylphenoxy)phenyl] methyl-piperidine, hydrochloride (36% yield, hygroscopic), (+/-)-4-[phenoxy)(4-chlorophenyl)]methyl-piperidine, hydrochloride (72% yield, m.p. 80 0 C (+/-)-4-[(4-benzoylphenoxy)phenyl]methyl-piperidine, hydrochloride (74% yield, m.p. 70 0 C and (+/-)-4-[(4-trifluoromethoxy)phenyl]methyl-piperidine, fumarate (58% yield, m.p. 76 0
C
Example 3 (+/-)-4-[(4-fluorophenoxy)phenyl]methyl-piperidine, sulfate An NaH (1.95 g, 60% mineral water) suspension in 20 mL of dimethylsulfoxide (DMSO) was 20 treated with a solution of (+/-)-4-(phenylhydroxy)methyl- I -piperidinecarboxylic acid, 1,1dimethyl-ethylester (13.8 g, 47 mmol) in 36 mL of DMSO. Potassium benzoate (7.5 g, 47 mmol) and 1.4-difluorobenzene (6.1 mL, 56 mmol) were added, and the reaction mixture was heated to 0 C until the starting substance disappeared. This was then treated with saturated aqueous NaCI and water solution, and extracted with ethyl ester. The organic phase evaporation residue was 25 treated with methanol (200 mL) and aqueous HCI 200 mL) solution and refluxed for an hour. The product was isolated with the usual methodology, yielding an oil (9.6 g, 72% yield).
RMN-'H (CDC 3 displayed a signal at 4.70 ppm J= 7.1 Hz, CHOAr) and RMN-'C (CDC 3 a signal at 85.0 ppm corresponding to CHOAr carbon. The oil was treated with a 1.85 mL conc.
**H
2 S0 4 solution in 90 mL of water, yielding the sulfate as a solid with a m.p. 118-120 0 C yield).
Example 4 (+/-)-4-[(3-fluorophenoxy)phenyl]methyl-piperidine, sulfate An NaH (0.40 g, 60% mineral water) suspension in 6 mL DMSO was treated with a solution of (+/-)-44(phenylhydroxy)methyl-1-piperidinecarboxylic acid, 1,1-dimethyl-ethylester (2.55 g, 8.75 mmol) in 6 mL of DMSO. Potassium benzoate (1.35 g, 8.43 mmol) and 1.3-difluorobenzene (1.05 -7mL, 10.6 rnol) wvere added, and the reaction mixture was heated to 85'C until the starting substance disappeared. It was then treated with saturated aqueous NaCI and water solution, and.
extracted with ethyl ester. The organic phase evaporation residue was treated with methanol rnL) and aqueous HCI 30 mL) solution and refluxed for an hour. The usual reaction working process yielded 2.16 g of an amber oil (88% yield). RMN- 1 H (CDCI 3 displayed a signal at 4.78 ppm J 6.4 Hz, IR, CHOAr) and RMN- 1 3 C (CDCI 3 a signal at 84.6 ppm corresponding to CHOAr carbon. The oil was treated with a 0.20 mL conc. H 2 S0 4 solution in mL of water, yielding the sulfate as a solid with a m.p. =72-76 0
C.
The following compounds were analogously prepared: (+/-)-4-(phenoxyphenyl)methyl-piperidine, hydrochloride (73% yield, hygroscopic), (+/-)-4-[(4-cyanophenoxy)phenyl]methyl-piperidine, fumnarate (8 1% yield, m.p. =76'C -trifluorophenoxy)phenyl]methyl-piperidime, hydrochloride (72% yield, m.p. 5 8 0
C
(+/-)-4-[(4-bromophenoxy)phenyl]methyl-piperidine, sulfate (70% yield, mn.p. 99-1 03 0
C),
(+/-)-NN-dimethyl-4-[[(4-piperidinyl)phenyl]methyl]oxy-benzamide, hydrochloride (72% yield, m.p. =45'C (deliquescent)), (+/-)-4-[(4-nitrophenyloxy)phenyl]methyl-piperidine, hydrochloride (80% yield, m.p. 80'C (+/-)-4-[(4-chlorophenyl)(1-naphthyloxy)]methyl-piperidine, sulfate (72% yield, m.p. 186'C 20 1-naphthyloxy)phenyl]methyl-piperidine, sulfate (70% yield, m.p. 1 52 0 C (+/-)-4-[(2-fluorophenoxy)phenyl]methyl-piperidine, sulfate (72% yield, m.p. 76'C (+/-)-4-[(3-cyanophenoxy)phenyl]methyl-piperidine, hydrochloride (80% yield, m.p. 82 0 C .(+/-)-4-[(3-chlorophenoxy)phenyl]methyl-piperidine, sulfate (60% yield, mn.p. 101-104'C), (+/-)-4-[(2-trifluoromethylphenoxy)phenyl]methyl-piperidine, sulfate (80% yield, m.p. 110 0
C
25 (+/-)-4-[(2-cyanophenoxy)phenyl]methyl-piperidine, oxalate (80% yield, mn.p. =105'C (+/-)4-[[(2biphenyl)oxy]phenyl~methyl-piperidine, hydrochloride (84% yield, m.p. 84-87 0
C),
(+/-)-4-[[(4-biphenyl)oxylphenyl]methyl-piperidine, hydrochloride (82% yield, m.p. 1DOT 0 (+/-)-4-[(3-bromophenoxy)phenyl]methyl-piperidine, sulfate (75% yield, mn.p. =98'C (+/-)-4-[(4-iodophenoxy)phenyl]methyl-piperidine, sulfate (57% yield, rn.p. =1051C (+/-)-4-[(3-iodophenoxy)phenyllmethyl-piperidine, sulfate (37% yield, mn.p. 127*C ,5-difluorophenoxy)phenyl]methyl-piperidine, sulfate (86% yield, m.p. =206-208*C), (+/-)-4-[(3-fluoro-2-methylphenoxy)phenyl]methyl-piperidine, sulfate (80% yield, m.p. 1 25 0
C
-chloro-4-cyanophenoxy)phenyl]methyl-piperidine, hydrochloride (70% yield, rn.p. 125-C (+/-)-4-[(5-chloro-2-methylphenoxy)phenyljmethyl-piperid me, sulfate (75% yield, m.p. 1051C (±/-)-4-[(3-chloro-2-methylphenoxy)phenyl]methyl-piperidine, sulfate (89% yield, m.p. 130 0
C
(+/-)-4-[(3,4-dichlorophenoxy)phenyl]methyl-piperidine, sulfate (91% yield, rn.p. 108'C -methoxy-5-luorophenoxy)phenyl]methyl-piperidine, hydrochloride (65% yield, rn.p. 200-203 0 C and -fluoro-5-cyanophenoxy)phenyl]methyl-piperidine, hydrochloride (76% yield, m.p.
Example Resolution of (+/-)-4-[(3-fluorophenoxy)phenyl]methyl-piperidine 4.45 g of L-(-)-dibenzoyltartaric acid were added over 7.1 g (25 mmol) of fluorophenoxy)phenyl]methyl-piperidine dissolved in 175 mL of ethanol A white solid was obtained 212'C which was treated with aqueous NaOH solution and extracted with chloroform, yielding the levorotary isomer (96% ee, m.p. 59-62'C, [a154 6 11.4, c 0.576, CHCI 3 The filtrate liquids obtained were concentrated and the free base was extracted by treatment with 20 aqueous NaOH solution and chloroform. The product obtained, dissolved in ethanol, was treated with D-(+)-dibenzoyltartaric acid using the preceding process. A white solid was obtained 208'C which was treated with aqueous NaOH solution and extracted with chloroform, yielding the dextrorotary isomer (98% ee, m.p. 59-62 0 G, [a]54 6 11.4, c 0.618, CHC13) 25 The following compounds were analogously prepared: o: o. (+)-4-[(4-fluorophenoxy)phenyl]methyl-piperidine (96% ee, m.p. 100-102 0 C, [a 546 14, c 0.259, CHC 3 o o :(-)-4-[(4-fluorophenoxy)phenyl]methyl-piperidine (96% ee, m.p. 100-102 0 C, [a ]546 14, c 0.237, CHCI 3 (+)-4-[(4-trifluoromethylphenoxy)phenyl]methyl-piperidine, sulfate (96/ ee, m.p. 85CG [a 1365+ 17.8, c 0.556, CHC 3 (-)-4-[(4-trifluoromethylphenoxy)phenyl]methyl-piperidine, sulfate (96% ee, m.p. 85 0 C [a] 365 15.5, c 0.508, CHCl 3 (+)-4-[(4-bromophenoxy)phenyl]methyl-piperidine (96% ee, m.p. 129-13 1 0 C [a36 54, c 1.012, CHC1 3 -9- (-)-4-[(4-bror-nophenoxy)phlenyljjmnethlyl-piperidine (95% ce, rn.p. =129-13l 0 'C [a] 436 54. 1, c =1.048, CHCI 3 -ch lorophenoxy)phienyl]i methyl-piperidine, methanosulfate (98% ee, m p. 200-202'C [a]1 365 14.6, c 0.646, CHCI 3 (-)-4-[(3-chlorophenoxy)phenyl] methyl-piperidine, methanosulfate (99% ee, m.p. 200-202'C [a]1 365 13.6, c =0.690, CHCI 3 (+)-4-[(3-cyanophenoxy)phenyl]methyl-piperidine, hydrochloride (95% ee, m.p. 70'C [a 1436 26.5, c 0.600, CHCI 3 (-)-4-[(3-cyanophenoxy)phenyl]methyl-piperidine, hydrochloride (98% ee, m.p. 70'C [a 1365 27.1, c=O.680, CHC 3 (+)-4-[(3,5-difluorophenoxy)phenyl]methyl-piperidine, sulfate (96% ee, m.p. 78'C [a]1 436 19.4, c 0.80, CHCI 3 (-)-4-[(3,5-difluorophenoxy)phenyl]methyl-piperidine, sulfate (98% ee, m.p. 78'C [X] 436 19.8, c 0.724, CHCI 3 (+)-4-[(3-fluorophenoxy)(3-fluorophenyl)]methyl-piperidine, hydrochloride (96% ee, m.p. [at 156 15, c 0. 183, CHCI1 3 and (-)-4-[(3-fluorophenoxy)(3-fluorophenyl)]methyl-piperidine, hydrochloride (95.4% ee, m.p.
78 0 C [a]1 546 16, c 0. 17, Gild1 3 Example 6 (+)-4-[(4-fluorophenoxy)phenyl]methyl-piperidine 4-benzoyl-piperidine (2.0 g, 10.6 mmol) was added over a solution of 6.8 g of chlorodiisopinocanfeilboran (21.25 mmol) in dichloromethane (20 mL, dry) cooled -down to 3-4*C. After reacting for 72 h, 2.0 mL of acetaldehyde (35.46 mmol) were added and stirred at room temperature for 3 h. 24 mL of an aqueous NaOil (6N) solution, dichioromethane and saturated aqueous NaCl solution were added. The phases were separated and the usual treatment of the organic phase provided -phenyl-4-piperidinemethanol as a white solid with a m.p. 64-66 0 C in a 90% yield (84% ee).
1.8 g of aminoalcohol -phenyl-4-piperidinemethanol (9.6 mmol) were dissolved in methanol mL). The solution was cooled down to 0 0 C and a diterbutyl dicarbonate ((Boc) 2 0) (2.5 g, 30 11.27 mmol) solution was added dropwise to 10 mL of methanol. The mixture was stirred for 24 h at room temperature, the methanol was concentrated, water was added and extracted with dichloromethane. The usual treatment of the organic phase provided the desired alcohol as a slightly coloured oil in a 93% yield.
The alcohol prepared above (2.7 g, 9.3 mmol) dissolved in DMSO (25 mL) was added over an Nail 0.6 g) suspension in DMSO (5 mL). Potassium benzoate (1.53 g, 9.63 mmol) and 1,4difluorobenzene (1.3 mL, 11.9 mmol) were added and the mixture was heated (70-75 0 C) until the starting substance disappeared. The reaction mixture was poured into water and saturated aqueous NaCI solution, and extracted with ether. The oil obtained was refluxed with a mixture of methanol mL) and an aqueous hydrochloric acid (40 mL) solution for Ih. Isolation of the product using the customary methodology provided (+)-4-[(4-fluorophenoxy)phenyl]methyl-piperidine as an oil in a 54% yield. Treatment of 0.5 g (1.75 mmol) of this oil with D-dibenzoyltartaric acid in ethanol 30 mL) provided a precipitate which was filtered 198-199°C). The aminoether was released yielding a white solid with a 96% ee, m.p. 102-104 0 C, and [a] 546 15, c 0.105, CHC1 3 The following compounds were analogously prepared: (+)-4-[(4-nitrophenoxy)phenyl]methyl-piperidine, hydrochloride (96% ee, m.p. 55°C [a]436 36, c 0.045, Ethanol) (-)-4-[(1-naphthyloxy)phenyl]methyl-piperidine, hydrochloride (98% ee, m.p. 65°C [a]546 180, c 0.080, CHCI 3 and (+)-4-[(2-fluorophenoxy)phenyl]methyl-piperidine, sulfate (97.6% ee, m.p. 105°C [a]54 6 31, c 0.081, CHCI3).
Example 7 (-)-4-[(4-fluorophenoxy)phenyl]methyl-piperidine 4-benzoyl-piperidine (7.35 g, 39.05 mmol) was added over a solution of 25 g of (-)-DIP-CI 20 (78.125 mmol) in dichloromethane (75 mL, dry) cooled down to 0-2°C. After reacting for 72 h, 5.2 mL of acetaldehyde (92.2 mmol) were added and stirred at room temperature for 3 h. 71 mL of an aqueous NaOH (6N) solution, dichloromethane and saturated aqueous NaCI solution were added. The phases were separated and the usual treatment of the organic phase provided phenyl-4-piperidinemethanol as a white solid with a m.p. 48-50 0 C in a 85% yield (86% ee).
25 2 g of aminoalcohol (-)-a-phenyl-4-piperidinemethanol (10.7 mmol) were dissolved in methanol (10 mL). The solution was cooled down to 0 C and a (Boc) 2 0 (2.6 g, 11.73 mmol) solution was added dropwise to 7 mL of methanol. The mixture was stirred for 20 h at room temperature, the methanol was concentrated, water was added and extracted with dichloromethane. The usual treatment of the organic phase provided the desired alcohol as a slightly coloured oil in a yield.
The alcohol prepared above (1.3 g, 4.5 mmol) dissolved in DMSO (10 mL) was added over an NaH 210 g) suspension in DMSO (5 mL). Potassium benzoate (715 g, 4.5 mmol) and 1,4difluorobenzene (0.75 mL, 6.86 mmol) were added and the mixture heated (70-75°C) until the starting substance disappeared. The reaction mixture was poured into water and saturated aqueous NaCI solution, and extracted with ether. The oil obtained was refluxed with a mixture of methanol -11 (17 mL) and an aqueous hydrochloric acid (17 mL) solution for lh. The usual working of the reaction provided (-)-4-[(4-fluorophenoxy)phenyl]methyl-piperidine as an oil in a 64% yield.
Treatment of this oil with L-dibenzoyltartaric acid in ethanol 35 mL) provided a precipitate which was filtered 193-194°C). The aminoether was released yielding a white solid with a 98% ee, m.p. 100-102 0 C, and [a] 546 14, c 0.2, CHCI 3 The following compounds were analogously prepared: (-)-4-[(4-nitrophenoxy)phenyl]methyl-piperidine, hydrochloride (98.7% ee, m.p. 59 0 C [a] 436 31, c 0.042, Ethanol) (+)-4-[(1-naphthyloxy)phenyl]methyl-piperidine, hydrochloride (94% ee, m.p. 115°C [a] 54 6 156, c 0.128, CHCI 3 and (-)-4-[(2-fluorophenoxy)phenyl]methyl-piperidine, sulfate (97.6% ee, m.p. 90 0 C [a ]46 31, c 0.140, CHCI 3 Example 8 (+/-)-4-[(3-fluorophenoxy)(3-fluorophenyl)]methyl-piperidine, sulfate a mixture of 4-cyanopiperidine (5 g, 40.92 mmol), (Boc) 2 0 (11.7 g, 53.7 mmol), sodium bicarbonate (11.7 g, 139.3 mmol) and water (117 mL) was stirred at room temperature for 17 h.
this was extracted with dichloromethane and the organic phase dried (anh. Na 2
SO
4 filtered and concentrated. The resultant oil was purified by flash chromatography (Still, Kahn, M., Mitra, A. J. Org. Chem. 1978, 43, 2923) yielding 4-cyano-l-piperidinecarboxylic acid, 1,1- 20 dimethyl-ethylester as a yellow oil in a 43% yield.
A Mg (0.5 g) suspension in ether (dry, 22mL) was treated with some millilitres (approximately 'A S* of the total) of a l-bromo-3-fluorobenzene (2.15 mL, 19.4 mmol) solution in ether (dry, 16 mL) and an iodine crystal. This was heated until a smooth reflux was observed and the colour disappeared. The rest of the solution was then added dropwise maintaining a mild reflux. With the 25 addition at an end, this was refluxed for 1 h 30 min and allowed to cool down to room temperature. A 4-cyano-l-piperidinecarboxylic acid ,1,1-dimethyl-ethylester (2.7 g, 12.84 mmol) solution was added dropwise to dry ether (27 mL) and the resultant mixture refluxed for 3 h. A saturated aqueous NH 4 CI (50 mL) solution was added and extracted with ether. The usual i treatment of the organic phase provided an oil which was purified by flash chromatography (Still, Kahn, Mitra, A. J Org. Chem. 1978, 43, 2923) yielding 2.4 g (61% yield) of 4-(3fluorobenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethyl-ethylester as a yellowish oil.
The product obtained above (2.4 g, 7.8 mmol) was dissolved in methanol (30 mL) and NaBH (0.2 g) dissolved in 3.5 mL water was added. The mixture was heated for 2 h in an oil bath (50-60 0
C)
and the product isolated in the usual manner, yielding (+/-)4-(3-fluorophenyl)hydroxy]methyl-1- -12piperidinecarboxylic acid, 1,1-dimethyl-ethylester as a very dense yellowish oil in quantitative yield.
A solution of the racemic alcohol prepared above (2.4 g, 7.8 mmol) in DMSO (25 mL) was added dropwise to an NaH (0.62 g) suspension in DMSO (15 mL). Potassium benzoate (1.53 g, 9.55 mmol) and 1,3-difluorobenzene (1.2 mL, 11.9 mmol) were added and the mixture was heated in an oil bath (65-70 0 C) until the starting substance disappeared. This was then poured into a mixture of saturated NaCI (50 mL) solution and water (39 mL). This was extracted with ether and the usual treatment of the ethereal phase provided an oil which was refluxed with a mixture of methanol (40 mL) and aqueous HCI (10 40 mL) solution for 1 h 30 min. The desired product (+/-)-4-[(3-fluorophenoxy)(3-fluorophenyl)]methyl-piperidine was obtained as an amber oil in a yield. RMN-'H (CDCI 3 of this product displayed a signal at 4.55 ppm J 6.1 Hz, CHOAr) and RMN- 3 C (CDC13) a signal at 83.9 ppm corresponding to CHOAr carbon. The oil prepared above was treated with a 0.22 mL cone. H 2 S0 4 solution in 16.5 mL of water, yielding the sulfate as a slightly coloured solid 158 0 C The following compounds were analogously prepared: (+/-)-4-[(2-fluorophenoxy)(3-fluorophenyl)]methyl-piperidine, hydrochloride (62% yield, m.p. 0 C) and (+/-)-4-[(4-fluorophenoxy)(3-fluorophenyl)]methyl-piperidine, hydrochloride (30% yield, m.p. 0
C).
I' ()PER Jg, cL~a,( d o2KI L12 12A- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form or suggestion that that prior art forms part of the common general knowledge in Australia.
It would be appreciated by a person skilled in the art the numerous variations and/or modifications may be made to the invention as shown the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
0oo *i
Claims (4)
1.4-substituted piperidines, of general formnula in which R, and R 2 are non-substituted aryl radicals or aryl radicals mono- or poly-substituted with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, trifluorornethioxy, trifluoromethyl, benzoyl, phenyl, nitro, amnino, aminoalkyl, aminoaryl and carbonylamino, and their pharmaceutically acceptable salts with inorganic acids and organic acids. OR 2
2. The 4-substituted piperidines of general formula according to claim 1 obtained as racemic mixtures and as pure enantiomers. The 4-substituted piperidines of general formula according to claim 1 or 2 listed hereinafter, obtained as racemnic mixtures or pure enantiomers, and their pharmaceutically acceptable salts:
4-(phenoxyphenyl)metbyl-piperidine, 4-[(4-fluorophenoxy)phenyljmethyl-piperidine 4-[(4-methoxyphenoxyX4-fluorophenyl)] methyl-piperidine 4-[(4-fluorophenoxy)(4-fluorophenyl)]methyl-piperidine 4-f (4-fluorophenoxy)(4-chlorophenyl)]methyl-piperidine 4-[(4-trifluoromethylpbenoxy)phenyl~methyl-piperidine 4-[(4-trifluoromethoxyphenoxy)(4-fluorophenyl)]methyl-piperidine 4-[phenoxy(4-chlorophenyl)]methyl-piperidine 4-[(4-benzoylphenoxy)phenyl)]methyl-piperidine 4-[(4-trifluoromethoxyphenoxy)phenyl]methyl-piperidine 4-[(4-cyanophenoxy)phenyl]methyl-piperidine 4-[(3-trifluorophenoxy)phenyl]methyl-piperidine b S y 4[3furpeoypey~ehlpprdn y 4-[(-bromrophenoxy)phenyl]medyl-piperidine P 'OPMRJgc%5936(499 cbim.doc-21VI lfAI2
14- N,N-dimethyl-4-[[(4-piperidinyl)phenyl]methyl]oxy-belzamfide 4-[(4-nitrophenyloxy)phenyllmethyl-piperidine 4-[(4-chlorophenylX I -naphthyloxy)]methyl-piperidine 4-[(lI -naphthyloxy)phenyl]methyl-piperidine 4-[(2-fluorophenoxy)phenyl]methyl-piperidine -cyanophenoxy)phenyl]methyl-piperidine 4-[(3-clhlorophenoxy)phenyljmethyl-piperidine 4-[(2-trifluoror-nethylphenoxy)phcenyl]metllyl-piperidine 4-[(2-cyanophenoxy)phenyl] methy I-piper id i e 4-[[(2-biphenyl)oxylphenyllmethyl-piperidine -fluorophenoxy)(3-fluorophenyl)]methyl-piperidine 4-[(2-fluorophenoxy)(3 -fluorophenyl)]methyl-piperidine 4-[(4-fluorophenoxy)(3 -fluorophenyl)]methyl-piperidine 4-[[(4-biphenyl)oxy]phenyl]methyl-piperidine 4-[(3-bromophenoxy)phenyl] methyl-piperidine 4-(-oopeoypenlmty-pprdn 4-[(3-iodophenoxy)phenyl]methyl-piperidiie 4-[(3,5-difluorophenoxy)phenyl] methyl-piperidine 4-[(3-fluoro-2-methylphenoxy)phenyl]methyl-piperidine 20 4-[(3-chloro-4-cyanophenoxy)phenyllmethyl-piperidine 4-[(5-chloro-2-methylphenoxy)phenyl]methyl-piperidine 4-[(3-chloro-2-methylphenoxy)phenylf~methyI-piperidine ,4-dicblorophenoxy)phenyl]methyl-piperidine 4-[(3-methoxy-5-fluorophenoxy)phenyllmethyl-piperidine, and 4-[(3-fluoro-5-cyanophenoxy)phenyl]methyl-piperidine. 4. Pharmaceutical compositions containing a therapeutically effective quantity of a compound of general formula in accordance with any one of claims I to 3, mixed with pharmaceutically acceptable excipients, to be orally, parenterally and topically administered. 5. A method for treating or preventing central nervous system disorders in humans consisting of administering a therapeutically effective quantity of a compound of general P OPER'Jgc-' (-99 claim doc-2 /I II2 formula in accordance with any one of claims 1 to 3 or composition of claim 4. 6. A method for treating or preventing depression, nervous bulimia, obsessive- compulsive disorders, alcohol addiction, anxiety, panic, pain, pre-menstrual syndrome, social phobia or migraine prophylaxis consisting of administering a therapeutically effective quantity of a compound of general formula in accordance with any one of claims 1 to 3 or composition of claim 4. 7. 4-substituted piperidines, methods for their manufacture or pharmaceutical compositions or methods of treatment involving/containing them, substantially as hereinbefore described with reference to the Examples. DATED this 29" day of November, 2002 S" Faes, Fabrica Espanola de Productos Quimicos Y Farmaceuticos, S.A. by DAVIES COLLISON CAVE 15 Patent Attorneys for the Applicant 0 g 15 Patent Attorneys for the Applicant
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| ES009802420A ES2157148B1 (en) | 1998-11-18 | 1998-11-18 | NEW 4-SUBSTITUTED PIPERIDINS. |
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| EP1513510A1 (en) * | 2002-05-30 | 2005-03-16 | Head Explorer A/S | The use of milnacipran for the treatment of tension-type headache |
| UA77536C2 (en) * | 2002-07-03 | 2006-12-15 | Lundbeck & Co As H | Secondary aminoaniline piperidines as mch1 antagonists and their use |
| US7521462B2 (en) | 2004-02-27 | 2009-04-21 | Eli Lilly And Company | 4-Amino-piperidine derivatives as monoamine uptake inhibitors |
| BRPI0512236A (en) | 2004-06-18 | 2008-02-19 | Wyeth Corp | processes for the preparation of 6-alkyl-5-arylsulfonyl dihydrophenanthridines |
| EP1854785A1 (en) * | 2006-05-12 | 2007-11-14 | Faes Farma, S.A. | 4-[(3-fluorophenoxy)phenylmethyl]piperidine methanesulfonate: uses, process of synthesis and pharmaceutical compositions |
| US20100120858A1 (en) * | 2006-08-23 | 2010-05-13 | Pfizer Inc. | Piperidine Derivatives |
| CA2742105C (en) * | 2008-11-14 | 2016-09-13 | Theravance, Inc. | 4-[2-(2-fluorophenoxymethyl)phenyl]piperidine compounds |
| US20100267743A1 (en) * | 2009-04-15 | 2010-10-21 | Stangeland Eric L | 3-(phenoxypyrrolidin-3-yl-methyl)heteroaryl, 3-(phenylpyrrolidin-3-ylmethoxy)heteroaryl, and 3-(heteroarylpyrrolidin-3-ylmethoxy)heteroaryl compounds |
| EP2390248A1 (en) | 2010-05-24 | 2011-11-30 | Faes Farma, S.A. | Flufenoxine derivatives for the treatment and prevention of amiloyd pathologies |
| MX2012013581A (en) | 2010-05-24 | 2013-02-15 | Faes Farma Sa | Flufenoxine derivatives for the treatment and prevention of amiloyd pathologies. |
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| JPH0615529B2 (en) * | 1985-04-01 | 1994-03-02 | エーザイ株式会社 | Novel piperidine derivative |
| JPH0840999A (en) * | 1994-08-04 | 1996-02-13 | Yamanouchi Pharmaceut Co Ltd | Fluoroindane derivative |
| CO5150201A1 (en) * | 1998-09-07 | 2002-04-29 | Hoffmann La Roche | PIPERIDINE DERIVATIVES |
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| Title |
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| CHEMICAL ABSTRACT VOL.106 NO.25 ABS. NO 213767 * |
| DERWNT PUBLICATION AN 1996-157056 * |
| MELONI ET AL., EUR. J. MED. CHEM. THERAP. VOL.19 NO.3 1984 * |
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